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WO1990000548A2 - Alcanolamines derivees utilisees comme agents cardiovasculaires - Google Patents

Alcanolamines derivees utilisees comme agents cardiovasculaires Download PDF

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Publication number
WO1990000548A2
WO1990000548A2 PCT/EP1989/000807 EP8900807W WO9000548A2 WO 1990000548 A2 WO1990000548 A2 WO 1990000548A2 EP 8900807 W EP8900807 W EP 8900807W WO 9000548 A2 WO9000548 A2 WO 9000548A2
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WO
WIPO (PCT)
Prior art keywords
compound
amino
hydroxy
phenoxy
imidazol
Prior art date
Application number
PCT/EP1989/000807
Other languages
English (en)
Other versions
WO1990000548A3 (fr
Inventor
Randall Edward Lis
William Carl Lumma
Thomas Kenneth Morgan
Klaus Nickisch
Ronald Andre Wohl
Original Assignee
Schering Aktiengesellschaft Berlin And Bergkamen
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Schering Aktiengesellschaft Berlin And Bergkamen filed Critical Schering Aktiengesellschaft Berlin And Bergkamen
Priority to JP1507740A priority Critical patent/JPH07119193B2/ja
Publication of WO1990000548A2 publication Critical patent/WO1990000548A2/fr
Publication of WO1990000548A3 publication Critical patent/WO1990000548A3/fr

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Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/16—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms
    • C07D295/18—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms acylated on ring nitrogen atoms by radicals derived from carboxylic acids, or sulfur or nitrogen analogues thereof
    • C07D295/182—Radicals derived from carboxylic acids
    • C07D295/192—Radicals derived from carboxylic acids from aromatic carboxylic acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P9/00—Drugs for disorders of the cardiovascular system
    • A61P9/06—Antiarrhythmics
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/08—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms
    • C07D295/084—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings
    • C07D295/088—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly bound oxygen or sulfur atoms with the ring nitrogen atoms and the oxygen or sulfur atoms attached to the same carbon chain, which is not interrupted by carbocyclic rings to an acyclic saturated chain
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/04—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms
    • C07D295/12—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms
    • C07D295/135—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with substituted hydrocarbon radicals attached to ring nitrogen atoms substituted by singly or doubly bound nitrogen atoms with the ring nitrogen atoms and the substituent nitrogen atoms separated by carbocyclic rings or by carbon chains interrupted by carbocyclic rings

Definitions

  • This invention relates to novel derivatized alkanolamines and their use as cardiovascular agents. More specifically, it deals with al kanolamines derivatized by at least imidazol-1-ylphenyl or alkylsulfonaminophenyl
  • the invention also relates to p ha rmaceutical compositions containing such compounds and their usefulness in cardiovascular therapy.
  • this invention relates to novel derivatized alkanolamines and their pharmaceutically acceptable salts. Particularly, this invention relates to the novel compounds defined by the following Formula I:
  • Q is defined as (C 1 -C 4 )-SO 2 -NH- or
  • x is the integer 0 or 1
  • A is defined as
  • ALK is -(CH 2 ) r - or -(CH 2 ) w .
  • R is hydrogen, lower alkyl, 2-p ropenyl or lower-alkoxyloweralkkyl.
  • R 1 , R 2 , and R 3 are the same or different and selected from hydrogen, lower alkyl, lower alkoxy,
  • r is an integer of 1-4;
  • w is an integer of 1-3;
  • p is an integer of 1-3 and
  • t is an integer of 2-5.
  • R 4 is hydrogen or lower alkyl
  • contemplated as part of this invention are the pharmaceutically acceptable salts of the compounds of Formula I.
  • Useful acids for this purpose include both inorganic and organic acids such as hydrochloric,
  • methanesul fonic methanesul fonic
  • p-toluenesul fo ⁇ ic acids methanesul fonic, and p-toluenesul fo ⁇ ic acids.
  • lower alkyl shall refer to a straight or branched chain of from 1 to 4 carbon atoms
  • lower alkoxy shall refer to a straight or branched chain of from 1 to 4 carbon atoms
  • loweralkoxy-loweralkyl shall be taken to mean a straight or branched chain alkoxy/alkyl of from 1 to 4 carbon atoms
  • halogen shall be taken to mean fluorine, chlorine, bromine or iodine.
  • Preferred classes of compounds embodied by this invention are those of the above general Formula I and having the following characteristics: a) when A is -O-ALK-NH- and Q is
  • the compounds of this invention may be prepared by various reactants and processes known in the art. Illustrative but not limiting as the reactants and processes utilized for the preparation of the compounds of the invention are the following Schemes A-H and J: As depicted in Scheme A, treating methyl aminobenzoates 1 under typical Debus conditions (NH 4 OH, formaldehyde and glyoxal) affords methyl imidazolylbenzoates 2. Reaction of methyl aminobenzoates 1 with various alkvlsulfonyl chlorides in pvridine and methylene chloride, usually at about 0°C, gives methyl
  • Acid chloride formation follows when the sodium salt 3 is treated with thionyl chloride (neat) or in refluxing toluene.
  • Amides 5 are prepared when acid chlorides 4 are treated with 1-b e n zy l p ip e r a z i n e in a solvent such as tetrahydrofuran .
  • Hydrogenolysi s of the benzyl group occurs when the amides 5 are treated with hydrogen gas and a catalyst such as palladium on carbon. Common solvents for this hydrogenolysis are water, ethanol, methanol and various mixtures thereof.
  • Compounds 7 of this invention are prepared when amide 6 is mixed with known in the art epoxides in methanol.
  • Compounds 9 are prepared by treating amides 6 with ⁇ -haloketones and Huenigs base in
  • aminobenzonitriles 10 Treatment of aminobenzonitriles 10 under typical Debus conditions give imidazolylbenzonitriles 11.
  • Aminobenzonitriles 10 can be alkylsulfonylated giving 11, using various alkylsulfonylchlorides in pyridine and methylene chloride. Reduction of the cyano moiety of 11 using hydrogen gas ( ⁇ 50 psi) and a Raney-Nickel catalyst in ammonia/methanol produces
  • nitrophenal kyl halides 16 are treated with sodium phthalimide in a solvent such as dimethyl formamide and give nitrophthal imides 17.
  • Reduction of the nitro moiety by the method of Bellamy (SnCl 2 , EtOH) gives aminophthalimides 18 after work up.
  • Imidazole formation via the Debus reaction (NH 4 OH, formaldehyde, glyoxal) follows to give 19.
  • Alkylsulfonylamino derivatives 19 are prepared by treatment of 18 with various alkylsulfonyl chlorides in pyridine and methylene chloride. Cleavage of the
  • imidazole 22 is formed.
  • Treating 21 with various alkylsulfonic anhydrides in a solvent such as acetonitrile produces a l ky l s u l f o ny l am id e s 22.
  • Compounds 26 are prepared by treating 23 with ⁇ -haloketones and Huenig's base in acetonitrile and subsequently reducing the ketone moiety of 25 using standard reduction conditions (H 2 , Pd-C, MeOH/H 2 O).
  • 3-imidazolyl derivatives 31 and 33 are prepared by analogous synthetic methods to those used for 24 and 26 via Scheme E. The only difference is that compound 27 is produced from the treatment of 3-nitroaniline with N,N-bis(2-chloroethyl)benzylamine
  • acetonitrile yields dibenzyl amines 42.
  • Monodebenzylation of 42 can be achieved under standard hydrogenolysis conditions (H 2 , Pd-C, EtOH/H 2 O) to give benzylamines 43.
  • Complete debenzvl ation of 42 can be accomplished under mor vigorous conditions (H 2 , Pd(OH) 2 , HOAc, ⁇ 50 psi) and affords amines 44.
  • Amines 43 and 44 can be carried through the same synthetic sequences as amines 36 and 35 (Scheme F) to give compounds 45 and 47 of this invention.
  • Dibenzylamines 49 can be prepared by reacting various dibenzyldiamines with either benzenesulfonyl chlorides or benzoyl chlorides 48 in a solvent such as tetrahydrofuran (Scheme H). Compounds 49 can be carried through the same sequences as compounds 42 (Scheme G) to produce compounds 52 and 54 of this invention.
  • novel alkanolamines of this invention derivatized by at least a imidazol-1-ylphenyl or alkylsulfonylaminophenyl moiety and their pharmaceutically acceptable salts are cardiovascular agents. Most especially within the aegis of cardiovascular pharmacology, these compounds have been specifically designed to provide a combination beta- adrenergic blockade with electrophysiologic activity to selectively prolong cellular refractoriness. According to the Vaughan Williams classification, such agents would have Class II/Class III antiarrhythmic effect. Such combination contains those therapeutic effects attributed to Class II and Class III antiarrhythmic agents singly.
  • Class II agents are the ⁇ -adrenergic blocking agents, which so called ⁇ -blockers decrease the sensitivity of the cardiac tissue to catecholamines.
  • the catecholamines in excess can increase the electrical instability of the heart.
  • Class II agents are exemplified by propranolol, metoprolol, nadolol, timolol, atenolol, sotalol, acebutolol and nipradilol.
  • the Class III agents prolong the action potential duration of the heart thus increasing the time interval in which the heart is
  • VF ventricular fibrillation
  • arrhythmias can occur as a result of abnormalities in conduction and/or refractoriness.
  • a reentrant In a reentrant
  • a single cardiac impulse follows a circular pathway, allowing repeated excitation of the same tissue.
  • One approach to the abolition of such reentrant a rrhyt hmi a s is to further prolong the refractory period of cardiac cells, such that the impulse, upon returning to its point of origin, is met with refractory tissue and propagation of the impulse is stopped. This is clearly the therapeutic rationale behind the development of agents possessing Class III activity.
  • beta-adrenergic blockers can reduce mortality from sudden cardiac death in post-infarction patients.
  • beta-blockers work by decreasing the sensitivity of the heart to catechol amines, and thereby decrease the potential "triggering" event which leads to reentrant ventricular arrhythmias. The overall decrease in mortality from these studies is approximately 25%,
  • beta-adrenergic blockade when used alone offers no beneficial antiarrhythmic effect in the remainin majority of post-infarction patients.
  • Clinical data such as these highlight th e multiple etioloogies present in patients dying of sudden cardiac death ana the need for a more "broad spectrum” approach.
  • beta-blocking effect of sotalol begins at doses lower or equivalent to doses which produce its Class III actions.
  • the compounds of this invention are designed to have a more potent Class III action relative to their Class II potency in order to demonstrate a distinct advantage in the setting of reentrant ventricular arrhythmias.
  • the compounds of this invention have been tested for their Class III activity via in vitro el ectrophysiologic testing utilizing standard intracellular mic roelect rode techniques in the canine cardiac Purkinje fiber. They were then tested for reasonable ⁇ -adrenergic blocking activity as measured in the in vitro screens of isolated papillary muscle (inhibition of the inotropic response to
  • Affinity for ⁇ -receptors was determined versus 3 H- dihydroalprenolol in partially purified membrane fractions of canine ventricular muscle ( ⁇ 1 -affinity) and in partially purified membrane fractions of canine lung tissue ( ⁇ 2 -affinity). Reported is the concentration of test compound which inhibited the binding of 3 H-dihydroalprenolol (4.5 nM) by 50% (IC 50 ).
  • Sematilide sematilide (selective Class III agent), sotalol (Class II)
  • propranolol selective Class II agent, i.e., ⁇ -blocker
  • the physician has been provided with a simple chemical entity providing 2 effects tnereby mitigating the problems of multiple drug therapy, e.g. side effects, metabolic problems, drug interactions, etc. and the problems in patient compliance - different drugs, different therapeutic regimens.
  • the compounds whilst preferably utilized in the treatment of mammalian arrhythmias and most specifically used in the treatment of mammalian arrhythmias in need of combination Class II/III effects, possess some general cardiovascular properties. Some of the compounds may, due to the level of Class II effects, exhibit an anti-hypertensive effect.
  • the compounds of this invention may be administered orally or parenterally.
  • the dosage may be administered orally or parenterally.
  • administered will depend on the subject being treated, the route of administration and the type and severity of the arrhythmias being prevented or reduced.
  • the compound to be administered can be formulated by admixing with any of a number of suitable pharmaceutical diluents and carriers such as lactose, sucrose, starch powder, cellulose, calcium sulfate, sodium benzoate and the like. Such formulations can be compressed into tablets or can be encapsulated into gelatin capsules for convenient oral administration.
  • suitable pharmaceutical diluents and carriers such as lactose, sucrose, starch powder, cellulose, calcium sulfate, sodium benzoate and the like.
  • Such a capsule may contain one of the compounds of this invention for example, N-[4-[4-[2-hydroxy-3-(2-methylphenoxy)propyl]piperazin-1-]phenyl]-methanesulfonamide, N-[4-[2-hydroxy-3-[[2-[4-(1H-imidazol 1-yl)phenoxy]ethyl]amino]propoxy]phonyl]methanesulfonamide or N-[4-[1-hydroxy-2-[[2-[4-(1H-imidazol-1-yl)phenoxy]-ethyl]amino]ethyl]phenyl]methanesulfonamide in the amount of about 1 to about 500 mg.
  • Such formulation can be
  • a compound of this invention can be formulated as an intramuscular or
  • intravenous medicament but is not limited thereto.
  • cardiac arrhythmias it may be desirable to administer a compound of the invention by intravenous slow bolus in order to effect a rapid conversion to a normal sinus rhythm.
  • the normalized condition can then be maintained by oral administration.
  • the compounds of this invention can be formulated for parenteral administration with any of a number of
  • a typical formulation suited to intravenous or intramuscular administration may contain one of the compounds of this invention such as N-[4-[4-[2-hydroxy-3-(2-methy!phenoxy)propyl]piperazin-1-]-phenyl]methanesulfonamide in the amount of about 50 to 150 mg and a solubilizing agent and sufficient sterile water to bring the volume to a bo u t 5ml - 100ml .
  • Su c h f o rmu l at io n c a n be infused at a constant rate or injected one to four times per day or more often depending upon the particular
  • condition of the subject being treated.
  • the compounds of this invention may be formulated into sublingual lozenges or impregnated into fabric appliques for a type of transdermal application.
  • N-(4-Aminomethylphenyl)methanesulfonamide hydrochloride Saturate 450 mL methanol with ammonia gas and add 45 g
  • the excess ethyl enedi amine is removed in vacuo and the residue is triturated with H 2 O, filtered, and the water evaporated.
  • the residue is dissolved in ethanol and treated with excess HC1 gas to provide the title compound.
  • N-[2-[bis(Phenylmethyl)amino]ethyl]propanamide To a chilled solution of 5.0 g (21 mmol) N,N-dibenzylethylenediamine and 30 mL (21 mmol) triethylamine in 20 mL THF is added 1.8 mL (21 mmol) propionyl chloride, dropwise. The temperature of the reaction mixture is maintained below 0°C during addition. The reaction mixture is stirred for 30 minutes at 0°C. After this time, the reaction mixture is filtered and the solvents are evaporated to give the product which can be purified via column chromatography.
  • reaction mixture is hydrogenated at 50 psi for 75 minutes. After this time, the reaction mixture is diluted with 100 mL methanol, filtered and the solvents are evaporated to yield the title compound.
  • N-[4-[[2-Hydroxy-3-(3-methylphenoxy)propyl]aminomethyl]- phenyl]methanesulfonamide hydrochloride Heat a mixture of N-[4-(aminomethyl)phenyl]methanesulfonamide hydrochloride (15.0 g, 63.4 mmol) and 1,2-epoxy-3-phenoxypropane (10.41 g, 63.4 mmol) in 63.4 mL of IN KOH in methanol and 10 mL of water for about 3.5 h. Remove the solvent to afford crystals of the title
  • 10 g (37.5 mmol) N-(2-aminoethyl)-4-(1H-imidazol-1-yl)benzamide hydrochloride in 50 mL methanol and 5 mL water with 1.69 g (42 mmol) sodium hydroxide, add 8.59 g (41.2 mmol) 1,2-epoxy-3-[4-(2-methoxyethyl)phenyl]-propane. Heat the mixture to 60°C for about 18 h. Cool the reaction mixture to room temperature and remove the solvents in vacuo. The resulting oil is chromatographed on alumina (activity III) using CH 2 Cl 2 :MeOH, 98:2.
  • a solution of dicyclopropylmethanone-O-(oxiranylmethyl)oxime (28 mmol) in 50 mL of 9:1 MeOH:H 2 O is added to the hot solution and heated at reflux for two days.
  • the solvent is removed from the reaction mixture under reduced pressure, and the residue is partitioned between CH 2 Cl 2 and H 2 O. Th aqueous portion is extracted with CH 2 Cl 2 . a nd the combined organic portion are washed with brine and dried with
  • N-[4-[4-[2-Hydroxy-3-(3-methylphenoxy)propyl]piperazin- 1-yl]phenyl]methanesulfonamide dihydrochloride Heat a mixture of 5.0 g (19.6 mmol) N-[4-(piperazin- 1-yl)phenyl]methanesulfonamide and 3.22 g (19.6 mmol) 1,2-epoxy-3-(3-methylphenoxy)propane in 50 mL of methanol and 2 mL of water at reflux for about 8 h. Cool the reaction to room temperature and collect the precipitate. Dissolve the solid in ethanol and bubble hydrochloric acid gas through the solution until the pH is 2.0. Concentrate the solution in vacuo to give the title compound.
  • N-[4-[4-[2-Hydroxy-3-(2-methylphenoxy)propyl]piperazin- 1-yl]phenyl]methanesulfonamide hydrochloride Heat a mixture of 5.0 g (19 mmol) N-[4-(piperazin-1-yl)phenyl]methanesulfonamide and 3.5 g (21.3 mmol) 1,2-epoxy-3-(2-methylphenoxy)propane in 50 mL MeOH and 5 mL water. Reflux for 6 h. After this time, allow the
  • reaction mixture to cool to room temperature and filter the resulting precipitate. Dissolve the precipitate in excess methanolic HCl and concentrate in vacuo to provide the title compound which can be recrystallized from ethanol.
  • the reaction mixture is hydrogenated at 50 psi in a Parr Hydrogenator.
  • a Parr Hydrogenator Follow the progress of the reaction by thin-layer chromatography on silica gel (methylene chloride:methanol, 9:1).
  • the catalyst is filtered and the solvents are removed in vacuo. The isolated oil is taken up in
  • NMR (DMSO-d 6 ): ⁇ 2.98(s,3), 3.21(m,2), 3.44(t,2), 4.42(t,2), 5.03(d,1), 6.24(br s,1), 7.23(d,4), 7.37(d,2), 7.76(d,2), 7.87(s,1), 8.21(5,1), 9.12(br s,1), 9.50(br s,1), 9.60(s,1) and 9.84(s,1) ppm.
  • NMR (CDCl 3 ): 6 2.8-3.4(br s,2), 2.89(t,2), 2.90- 3.10(m,2), 3.200t,2), 3.42(s,3), 3.63(t,2), 4.06(d,2), 4.25(m,3), 6.92(d,2), 7.05(d,2), 7.19(d,2), 7.25(m,2), 7.35(d,2) and 7.85(s,l) ppm.

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  • Organic Chemistry (AREA)
  • Health & Medical Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Life Sciences & Earth Sciences (AREA)
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  • Heart & Thoracic Surgery (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
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  • General Health & Medical Sciences (AREA)
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  • Veterinary Medicine (AREA)
  • Acyclic And Carbocyclic Compounds In Medicinal Compositions (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)

Abstract

La présente invention se rapporte à de nouvelles alcanolamines dérivées représentées par la formule structurelle (I) et utiles comme agents cardiovasculaires. Est particulièrement décrite leur utilité comme agents cardiovasculaires comportant une action anti-arythmie. Le type d'action anti-arythmie décrite est une variété de combinaison de classe II/classe III. Des formules pharmaceutiques contenant de tels composés sont également décrites.
PCT/EP1989/000807 1988-07-13 1989-07-13 Alcanolamines derivees utilisees comme agents cardiovasculaires WO1990000548A2 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
JP1507740A JPH07119193B2 (ja) 1988-07-13 1989-07-13 心血管系医薬としてのアルカノールアミン誘導体

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
US07/218,195 US5051423A (en) 1988-07-13 1988-07-13 Derivatized alkanolamines as cardiovascular agents
US218,195 1988-07-13

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WO1990000548A2 true WO1990000548A2 (fr) 1990-01-25
WO1990000548A3 WO1990000548A3 (fr) 1990-05-03

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US (1) US5051423A (fr)
EP (1) EP0358284B1 (fr)
JP (1) JPH07119193B2 (fr)
AT (1) ATE157089T1 (fr)
CA (1) CA1328105C (fr)
DE (1) DE68928262T2 (fr)
ES (1) ES2107998T3 (fr)
GR (1) GR3025151T3 (fr)
WO (1) WO1990000548A2 (fr)

Cited By (11)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5202346A (en) * 1992-02-25 1993-04-13 American Home Products Corporation Piperidinyl and piperazinyl derivatives
US5254689A (en) * 1992-02-25 1993-10-19 American Home Products Corporation Piperdinyl and piperazinyl derivatives
US5286728A (en) * 1991-07-19 1994-02-15 Ciba-Geigy Corporation Amino-substituted piperazine derivatives
EP0611003A1 (fr) * 1993-02-09 1994-08-17 Merck & Co. Inc. Phénylsulfonamides substitués comme B3-agonistes selectives pour le traitement du diabète et de l'obésité
US5380726A (en) * 1993-01-15 1995-01-10 Ciba-Geigy Corporation Substituted dialkylthio ethers
US5384319A (en) * 1993-01-06 1995-01-24 Ciba-Geigy Corporation Aminoalkylphenyl compounds
WO2002032897A1 (fr) * 2000-10-20 2002-04-25 Pfizer Products Inc. Ethanolamines alpha-aryle et utilisation de ces dernieres en tant qu'agonistes du recepteur adrenergique beta-3
US6689888B2 (en) 2002-02-27 2004-02-10 Pfizer Inc. Processes and intermediates useful in preparing β3-adrenergic receptor agonists
US6689800B2 (en) 2002-02-27 2004-02-10 Pfizer Inc. β3-adrenergic receptor agonist crystal forms, processes for the production thereof, and uses thereof
US6864268B2 (en) 2002-02-27 2005-03-08 Pfizer Inc. β3 adrenergic receptor agonists
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EP0358284B1 (fr) 1997-08-20
US5051423A (en) 1991-09-24
JPH07119193B2 (ja) 1995-12-20
ATE157089T1 (de) 1997-09-15
DE68928262D1 (de) 1997-09-25
JPH03501617A (ja) 1991-04-11
CA1328105C (fr) 1994-03-29
ES2107998T3 (es) 1997-12-16
EP0358284A2 (fr) 1990-03-14
WO1990000548A3 (fr) 1990-05-03
EP0358284A3 (fr) 1990-06-20
GR3025151T3 (en) 1998-02-27
DE68928262T2 (de) 1998-04-02

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